Clinical Aspects of B Cell Immunodeficiencies: The Past, the Present and the Future

Abstract

B cells and antibodies are indispensable for host immunity. Our understanding of the mechanistic processes that underpin how B cells operate has left an indelible mark on the field of clinical pathology, and recently has also dramatically reshaped the therapeutic landscape of diseases that were once considered incurable. Evaluating patients with primary immunodeficiency diseases (PID)/inborn errors of immunity (IEI) that primarily affect B cells, offers us an opportunity to further our understanding of how B cells develop, mature, function and, in certain instances, cause further disease. In this review we provide a brief compendium of IEI that principally affect B cells at defined stages of their developmental pathway, and also attempt to offer some educated viewpoints on how the management of these disorders could evolve over the years.

Keywords: B cells; humoral immunity; immunodeficiency; inborn errors of immunity.

Figure 1

Flow cytometry−based assessment of BTK expression to aid in the clinical diagnosis of XLA. The histogram overlay plots reveal the presence and/or absence of BTK protein expression in the cytosol of the indicated cellular subsets. Circulating T cells, B cells and monocytes were identified by utilizing lineage−directed monoclonal antibodies targeting the surface expression of CD3, CD19 and CD64. Subsequently, cells were fixed, permeabilized and stained with a BTK−specific monoclonal Ab (clone 53/BTK; BD Biosciences, San Jose, CA, USA) to facilitate the detection of cytosolic BTK (blue histograms). The numbers listed in parentheses adjacent to the cell subset label reflect the clinically−validated reference ranges (5th−95th percentiles) for that particular cell subset, derived from the background−subtracted median fluorescence intensity (MFI) of BTK expression. The numbers listed within each histogram overlay plot reflect the background−subtracted MFI of BTK expression for that specific cell subset for each donor. The histogram overlay plots for the carrier monocytes list the background−subtracted BTK MFI values, as well as the frequency (%) of the BTK(+) and BTK(−) monocytic populations. The specificity of the BTK signal was determined by also separately staining the cells with a dose−matched, isotype control Ab (pink histograms). T cells serve as an additional internal specificity control in the assay, as they lack BTK expression.

Figure 2

Listing of predominantly B cell associated IEI. This figure lists both the underlying genetic defects (in black) and name of the disease (in red), based on the 2019 International Union of Immunological Societies (IUIS) update, as well as the 2022 update on the classification of human inborn errors of immunity. * These defects can display both autosomal recessive (AR) as well as autosomal dominant (AD) patterns, and these patterns can affect the disease phenotype as well as the degree to which the different Ig isotypes and B cell numbers are decreased. ^# These variants can be considered disease−modifying rather than disease−causing, since healthy individuals can also harbor heterozygous variants of this gene. TF: transcription factor.

Figure 3

Representative genes targeting defined steps in the B cell maturation and differentiation pathways. Immune defects caused by the genes (labeled in red) are discussed in this report. * Although these genes are not included in the latest IUIS classification of predominantly Ab deficiencies, they are associated with defects in Ab isotype switching (CD40LG), and immune dysregulation, manifesting as early−onset hypogammaglobulinemia (CTLA4 and LRBA), which is part of a spectrum of widespread immune aberrations that also includes autoimmunity. † These cell populations reside in the bone−marrow.